The KRAS G12D mutation is a common subtype found in RAS mutant cancers, but there have been no reported findings from clinical trials regarding inhibitors specifically designed for KRAS G12D. HRS-4642 is the first KRAS G12D inhibitor approved for clinical use in China.

The study aims to assess the safety and tolerance of novel KRAS G12D inhibitor HRS-4642 in patients with advanced solid tumors carrying the KRAS G12D mutation. Its objective is to determine the maximum tolerated dose (MTD) and/or an effective dose for the various groups of subjects being investigated. At data cutoff on August 4, 2023, 18 patients were enrolled (lung adenocarcinoma n=10, colorectal adenocarcinoma n=5, appendiceal mucinous adenocarcinoma, ovarian cancer, and pancreatic cancer n=1 each). Patients had received a median of 3 lines of prior treatment. No dose-limiting toxicities were observed and the MTD was not reached yet. Grade ≥3 adverse events (AEs) were observed in 9 patients. 6 patients had grade ≥3 treatment-related AEs (TRAEs), being hypercholesterolemia, increased lipase, and anemia. No dose-dependent trend was observed in the incidence of AEs. Serious TRAEs were observed in one. No patients discontinued treatment or died due to TRAEs. 13 patients with baseline target lesions had at least one post-baseline assessment, and one NSCLC patient at 200 mg had a partial response. 11 patients had stable disease, and 6 experienced target lesion shrinkage, including lung and colorectal cancers. HRS-4642 exposure was approximately proportional to the dose with a half-life of around 40 hours. These findings provide hope through HRS-4642, which is a very precise inhibitor created for KRAS G12D.

KOL insights

“The first-in-human Phase I study of the novel KRAS G12D inhibitor, HRS-4642, in patients with advanced solid tumors harboring KRAS G12D mutation has shown promising results. Notably, we observed one partial response in NSCLC and an impressive disease control rate of 78%. Furthermore, the overall safety profile is quite reassuring.” - Medical Oncologist, Hospital General Universitario Gregorio Marañón, Spain

Conclusion

HRS-4642, the first KRASG12D inhibitor, has shown promising clinical outcomes with a favorable safety profile. The drug was well tolerated, even at doses up to 300 mg administered weekly, with no dose-limiting toxicities (DLTs) observed. Notably, all treatment-related adverse events (TRAEs) were laboratory abnormalities and did not lead to dose reductions, treatment discontinuations, or fatalities.

Preliminary efficacy was demonstrated in heavily pretreated solid tumors containing the KRASG120 mutation, with one patient achieving a partial response (PR) and a disease control rate (DCR) of 77.8% observed across all tumors and a remarkable 90% in non-small cell lung cancer (NSCLC).

The ongoing dose-escalation and the anticipated dose expansion phase suggest that HRS-4642 may continue to exhibit its potential in treating these challenging cancers. These early findings are encouraging and warrant further investigation, raising optimism for the development of HRS-4642 as a promising therapy for KRASG12D-mutated solid tumors.

Before the approval of the first drug LUMAKRAS (licensed for KRAS G12C mutant NSCLC), KRAS mutations were historically thought to be undruggable. DelveInsight estimates that the total metastatic KRAS-mutated NSCLC market size in the 7MM is expected to reach around USD 8 billion by 2032. KRAS mutations are seen most frequently in pancreatic cancer, followed by CRC and NSCLC. The most frequent KRAS variant observed in NSCLC is G12C. In addition, the most common KRAS variation in CRC and pancreatic cancer is G12D.

#Other includes A146T, A146V, G12A, G12F, G12S, G13C, G13V, K117N, KRAS amplification, Q61H, Q61L, Q61R

 

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the KRAS Inhibitors Market Insights and Forecast Report